Research Article: IL-17 can be protective or deleterious in murine pneumococcal pneumonia

Date Published: May 29, 2018

Publisher: Public Library of Science

Author(s): Neil D. Ritchie, Ryan Ritchie, Hannah K. Bayes, Tim J. Mitchell, Tom J. Evans, Elaine I. Tuomanen.


Streptococcus pneumoniae is the major bacterial cause of community-acquired pneumonia, and the leading agent of childhood pneumonia deaths worldwide. Nasal colonization is an essential step prior to infection. The cytokine IL-17 protects against such colonization and vaccines that enhance IL-17 responses to pneumococcal colonization are being developed. The role of IL-17 in host defence against pneumonia is not known. To address this issue, we have utilized a murine model of pneumococcal pneumonia in which the gene for the IL-17 cytokine family receptor, Il17ra, has been inactivated. Using this model, we show that IL-17 produced predominantly from γδ T cells protects mice against death from the invasive TIGR4 strain (serotype 4) which expresses a relatively thin capsule. However, in pneumonia produced by two heavily encapsulated strains with low invasive potential (serotypes 3 and 6B), IL-17 significantly enhanced mortality. Neutrophil uptake and killing of the serotype 3 strain was significantly impaired compared to the serotype 4 strain and depletion of neutrophils with antibody enhanced survival of mice infected with the highly encapsulated SRL1 strain. These data strongly suggest that IL-17 mediated neutrophil recruitment to the lungs clears infection from the invasive TIGR4 strain but that lung neutrophils exacerbate disease caused by the highly encapsulated pneumococcal strains. Thus, whilst augmenting IL-17 immune responses against pneumococci may decrease nasal colonization, this may worsen outcome during pneumonia caused by some strains.

Partial Text

Streptococcus pneumoniae, or the pneumococcus, is a major cause of pneumonia, meningitis, sepsis and otitis media, with a highly significant global morbidity and mortality [1, 2]. Initially, the microbe colonizes the nasopharynx, where it may remain asymptomatically for weeks to months before eventual clearance [3]. However, following such colonization, in some individuals the bacterium can then invade other body compartments, such as the lower respiratory tract to cause pneumonia, or can spread to blood, myocardium or cerebrospinal fluid [4, 5]. The microbe has a polysaccharide capsule, which is an essential virulence factor, protecting the organism against neutrophil phagocytosis and other immune effector mechanisms [6]. The capsular serotype, of which there are over 90 different types, is an important determinant of many features of pneumococcal colonization and disease [7]. A number of studies have found stable differences between serotypes in the frequency with which they colonize the nasopharynx compared to their recovery in cases of invasive pneumococcal disease, usually blood [8]. This allows classification of pneumococci into “invasive” versus “non-invasive strains”, although serotype is not the only factor influencing invasiveness. Although less likely to cause invasive disease, when they do invade, these strains are more frequently associated with fatal outcome [9]. Those strains associated with fatal outcome are more heavily encapsulated in vitro. So-called “non-invasive” strains such as capsular serotype 3 are, however, commonly isolated from patients with non-bacteremic pneumonia [10] or from para-pneumonic effusions [11]. As suggested by Weinberger et al [9], this may reflect the difficulty with which heavily encapsulated strains may cross epithelial barriers, but by providing protection against neutrophil phagocytosis, the large capsule may allow persistence in tissues where invasion has occurred, accounting for the increased mortality produced by such strains.

We have shown here that protective versus harmful effects of IL-17 in the innate immune response to acute pneumococcal infection in a murine model are critically dependent on pneumococcal strain. IL-17 is protective against pulmonary infection with TIGR4, a representative invasive strain of relatively low capsular thickness, but has an adverse effect on outcome following infection with 2 separate highly encapsulated strains (SRL1 and SRL2) that are representative of strains of lower invasive potential. Since neutrophil depletion improved survival following infection with these strains, we believe that the deleterious effect of IL-17 against these strains in this model is mediated by neutrophils. This is also supported by the interactions of purified neutrophils with TIGR4 and SRL1, which show that the highly encapsulated SRL1 strain is better able to avoid neutrophil uptake and killing compared to TIGR4. Neutrophil-mediated damage has been implicated as a key pathogenic factor in adult respiratory distress syndrome [40] and contributing to tissue damage by bacterial and nematode infection [41, 42]. Neutrophil depletion enhanced survival in a model of pneumococcal infection caused by a non-hemolytic serotype 8 strain [43]. We propose that extensive neutrophil accumulation as seen in Fig 4, mediates enhanced tissue damage following pulmonary infection with highly encapsulated pneumococcal strains, allowing enhanced growth and passage of bacteria out of the lung and increasing mortality.